Scientists and clinicians face a number of challenges in their attempts to develop active agents that are in a form suitable for delivery to a patient. Active agents that are polypeptides, for example, are often delivered via injection rather than orally. In this way, the polypeptide is introduced into the systemic circulation without exposure to the proteolytic environment of the stomach. Injection of polypeptides, however, has several drawbacks. For example, many polypeptides have a relatively short half-life, thereby necessitating repeated injections, which are often inconvenient and painful. Moreover, some polypeptides may elicit one or more immune responses with the consequence that the patient's immune system may be activated to degrade the polypeptide. Thus, delivery of active agents such as polypeptides is often problematic even when these agents are administered by injection.
Some success has been achieved in addressing the problems of delivering active agents via injection. For example, conjugating the active agent to a water-soluble polymer has resulted in polymer-active agent conjugates having reduced immunogenicity and antigenicity. In addition, these polymer-active agent conjugates often have greatly increased half-lives compared to their unconjugated counterparts as a result of decreased clearance through the kidney and/or decreased enzymatic degradation in the systemic circulation. As a result of having a greater half-life, the polymer-active agent conjugate requires less frequent dosing, which in turn reduces the overall number of painful injections and inconvenient visits with a health care professional. Moreover, active agents that were only marginally soluble demonstrate a significant increase in water solubility when conjugated to a water-soluble polymer.
Due to its documented safety and approval by the FDA for both topical and internal use, poly(ethylene glycol) has been conjugated to active agents. When an active agent is conjugated to polyethylene glycol or “PEG”, the conjugated active agent is conventionally referred to as “PEGylated.” The commercial success of PEGylated active agents, such as PEGASYS® PEGylated interferon alpha-2a (Hoffmann-La Roche, Nutley, N.J.), PEG-INTRON® PEGylated interferon alpha-2b (Schering Corp., Kennilworth, N.J.), NEULASTA™ PEG-filgrastim (Amgen Inc., Thousand Oaks, Calif.), demonstrates that administration of a conjugated form of an active agent can have significant advantages over the unconjugated counterpart. PEGylated versions of certain small molecules, such as distearoylphosphatidylethanolamine (Zalipsky (1993) Bioconjug. Chem. 4(4):296-299) and fluorouracil (Ouchi et al. (1992) Drug Des. Discov. 2(1):93-105), have also been prepared. Harris et al. have provided a review of the effects of PEGylation on pharmaceuticals. Harris et al. (2003) Nat. Rev. Drug Discov. 2(3):214-221.
Despite these successes, conjugation of a polymer to an active agent is often challenging. For example, attaching a relatively long poly(ethylene glycol) molecule to an active agent typically imparts greater water solubility than attaching a shorter poly(ethylene glycol) molecule. However, some conjugates bearing such long poly(ethylene glycol) moieties have been known to be substantially inactive in vivo. It has been hypothesized that these conjugates are inactive due to the length of the poly(ethylene glycol) chain, which effectively “wraps” itself around the entire active agent, thereby blocking access to potential ligands required for activity.
The problem associated with inactive conjugates bearing relatively large poly(ethylene glycol) moieties has been solved, in part, by using “branched” forms of a polymer derivative. “mPEG2-N-hydroxysuccinimide” and “mPEG2-aldehyde,” as shown below, represent examples of branched versions of a poly(ethylene glycol) derivative.
wherein n represents the number of repeating ethylene oxide monomer units.
Although solving some of the issues associated with using relatively large polymers, branched versions of polymer derivatives also have problems. For example, the increased structurally complexity of branching often results in a concomitant increase in synthetic complexity and/or purification difficulties. As a result, there is an ongoing need in the art for more readily synthesized and/or purified polymer derivatives that can be conveniently used in conjugation reactions with active agents.